The hallmark of the aberrant cellular immune response in systemic lupus erythematosus (SLE) is T cell dysfunction (A. K. Dayal and G. M. Kammer, Arthritis Rheum. 39, 23 (1996); D. A. Horwitz, et al., in Dubois' Lupus Erythematosus., D. J. Wallace and B. H. Hahn, Eds. (Williams & Wilkins, Baltimore, 1997), chap. 10). An imbalance exists between exaggerated helper function and deficient cytotoxic/suppressor activity that promotes inappropriate B cell overproduction of immunoglobulins (Ig). The resulting polyclonal hypergammaglobulinemia is comprised of natural antibodies and pathogenic autoantibodies, including anti-native DNA. Formation of complement-fixing immune complexes in situ or their deposition on vascular endothelium, such as the renal glomerulus, initiates a chronic inflammatory response that leads to irreparable parenchymal damage, ultimately resulting in end-organ failure (R. P. Kimberly, in Arthritis and Allied Conditions: A Textbook of Rheumatology, W. J. Koopman, Ed. (Williams & Wilkins, Baltimore, 1997), chap. 27). Moreover, T cell dysfunctions predispose to recurrent, often life-threatening infections (A. G. Iliopoulos and G. C. Tsokos, Sem. Arthritis Rheum. 25, 318 (1996); C. A. Hunter and S. L. Reiner, Curr. Opin. Immunol. 12, 413 (2000)).
Two principal defects of T cell function in SLE are augmented expression of cell surface receptors and altered production of cytokines. CD40 ligand (CD154) expression is significantly increased and prolonged on both CD4+ helper (Th) and CD8+ cytotoxic/suppressor (Tc) subpopulations (M. Koshy, et al., J. Clin. Invest. 98, 826 (1996); A. Desai-Mehta, et al, J. Clin. Invest. 97, 2063 (1996)). This prolonged over-expression may be pathophysiologically significant, for binding of CD154 on Th cells to CD40 on B cells promotes B cell activation and may drive the polyclonal hypergammaglobulinemia. Moreover, Th2 cells over-produce IL-10 whereas Th1 cells under-produce IFN-γ. Heightened levels of IL-10 may profoundly modify the cellular immune response by (a) downregulating both IFN-γ and IL-2 production by Th1 cells; (b) inhibiting IL-12 generation and down-regulating expression of IL-12 receptors on Th1 cells; (c) up-regulating bcl-2 expression and preventing apoptosis of activated T cells; and, (d) promoting B cell growth, differentiation and autoantibody production. By contrast, deficient IFN-γ may significantly hinder cellular immunity in SLE by both impairing Tc-dependent cytotoxicity and altering antigen-presentation (B. S. Handwerger, et al., in Lupus: Molecular and Cellular Pathogenesis, G. M. Kammer and G. C. Tsokos, Eds. (Humana Press, Totowa, N.J., 1999), chap. 21).
While several treatments for SLE and other autoimmune diseases have been developed, none are entirely satisfactory. Hence, there remains a need for new ways to treat autoimmune diseases such as SLE.